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Dimeric interactions and complex formation using direct coevolutionary couplings.

dos Santos RN, Morcos F, Jana B, Andricopulo AD, Onuchic JN - Sci Rep (2015)

Bottom Line: Therefore a systematic way to extract dimerization signals has been elusive.For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively.This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827.

ABSTRACT
We develop a procedure to characterize the association of protein structures into homodimers using coevolutionary couplings extracted from Direct Coupling Analysis (DCA) in combination with Structure Based Models (SBM). Identification of dimerization contacts using DCA is more challenging than intradomain contacts since direct couplings are mixed with monomeric contacts. Therefore a systematic way to extract dimerization signals has been elusive. We provide evidence that the prediction of homodimeric complexes is possible with high accuracy for all the cases we studied which have rich sequence information. For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively. This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation. The identification of dimeric complexes can provide interesting molecular insights in the construction of large oligomeric complexes and be useful in the study of aggregation related diseases like Alzheimer's or Parkinson's.

No MeSH data available.


Related in: MedlinePlus

Predicted dimeric structures for 8 different proteins and families.The best inferred bound complexes have different topologies and sizes. These proteins have lengths ranging from 121–444 aa (mean 303 aa) and contain distinct folds as well as single and multidomain architectures (ketoacyl synthase and alcohol dehydrogenase). A notable case is the protein GAPDH for which the iRMSD has sub-angstrom resolution and the ketoacyl synthase with an RMSD = 1 Å. For the case of the isocitrate dehydrogenase we see that the dimeric interface shown on the top requires a conformational rearrangement in order for the helices to wrap around each other. This was only possible given the high number of coevolved contacts found around this area. See Supplementary Fig. S4 for more systems.
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f3: Predicted dimeric structures for 8 different proteins and families.The best inferred bound complexes have different topologies and sizes. These proteins have lengths ranging from 121–444 aa (mean 303 aa) and contain distinct folds as well as single and multidomain architectures (ketoacyl synthase and alcohol dehydrogenase). A notable case is the protein GAPDH for which the iRMSD has sub-angstrom resolution and the ketoacyl synthase with an RMSD = 1 Å. For the case of the isocitrate dehydrogenase we see that the dimeric interface shown on the top requires a conformational rearrangement in order for the helices to wrap around each other. This was only possible given the high number of coevolved contacts found around this area. See Supplementary Fig. S4 for more systems.

Mentions: Figure 2 depicts native contact maps of two different dimeric complexes: protein isocitrate dehydrogenase (2IV0) and glucose 6-phosphate isomerase (3FF1) along with the contact map of the predicted dimer structure. The native maps, shown in the upper triangular section of the plot, have two different types of contacts. Native monomeric contacts are colored in brown and native multimeric contacts are colored in orange. These maps also show the predicted dimeric contacts from DCA in black circles. The exact number of constrains used for each case depends on filtering the top 100 DCA pairs using a solvent accessibility criterion and by removing contacts around the monomeric structure (see Methods section). It has been suggested that these types of long distance couplings might be related to elastic interactions46 but this remains to be characterized. The number of couplings used in the simulations range from 30–75 for all the systems. Most of the remaining predicted contacts are part of the dimeric interface and are used as contact pairs described by a Gaussian potential (Supplementary Methods, Eqs 6–7). The lower triangular regions on the contact maps of Fig. 2 represent the contacts of the best-predicted complexes. The intra-domain contacts are shown in blue and the intermolecular contacts are shown in green. The reconstruction of these maps is highly accurate and recapitulates well both intra and inter-domain native interactions. The contact maps for the remaining proteins studied are shown in Supplementary Figs S2-3 and the estimated complexes are shown in Fig. 3 and Supplementary Fig. S4.


Dimeric interactions and complex formation using direct coevolutionary couplings.

dos Santos RN, Morcos F, Jana B, Andricopulo AD, Onuchic JN - Sci Rep (2015)

Predicted dimeric structures for 8 different proteins and families.The best inferred bound complexes have different topologies and sizes. These proteins have lengths ranging from 121–444 aa (mean 303 aa) and contain distinct folds as well as single and multidomain architectures (ketoacyl synthase and alcohol dehydrogenase). A notable case is the protein GAPDH for which the iRMSD has sub-angstrom resolution and the ketoacyl synthase with an RMSD = 1 Å. For the case of the isocitrate dehydrogenase we see that the dimeric interface shown on the top requires a conformational rearrangement in order for the helices to wrap around each other. This was only possible given the high number of coevolved contacts found around this area. See Supplementary Fig. S4 for more systems.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4559900&req=5

f3: Predicted dimeric structures for 8 different proteins and families.The best inferred bound complexes have different topologies and sizes. These proteins have lengths ranging from 121–444 aa (mean 303 aa) and contain distinct folds as well as single and multidomain architectures (ketoacyl synthase and alcohol dehydrogenase). A notable case is the protein GAPDH for which the iRMSD has sub-angstrom resolution and the ketoacyl synthase with an RMSD = 1 Å. For the case of the isocitrate dehydrogenase we see that the dimeric interface shown on the top requires a conformational rearrangement in order for the helices to wrap around each other. This was only possible given the high number of coevolved contacts found around this area. See Supplementary Fig. S4 for more systems.
Mentions: Figure 2 depicts native contact maps of two different dimeric complexes: protein isocitrate dehydrogenase (2IV0) and glucose 6-phosphate isomerase (3FF1) along with the contact map of the predicted dimer structure. The native maps, shown in the upper triangular section of the plot, have two different types of contacts. Native monomeric contacts are colored in brown and native multimeric contacts are colored in orange. These maps also show the predicted dimeric contacts from DCA in black circles. The exact number of constrains used for each case depends on filtering the top 100 DCA pairs using a solvent accessibility criterion and by removing contacts around the monomeric structure (see Methods section). It has been suggested that these types of long distance couplings might be related to elastic interactions46 but this remains to be characterized. The number of couplings used in the simulations range from 30–75 for all the systems. Most of the remaining predicted contacts are part of the dimeric interface and are used as contact pairs described by a Gaussian potential (Supplementary Methods, Eqs 6–7). The lower triangular regions on the contact maps of Fig. 2 represent the contacts of the best-predicted complexes. The intra-domain contacts are shown in blue and the intermolecular contacts are shown in green. The reconstruction of these maps is highly accurate and recapitulates well both intra and inter-domain native interactions. The contact maps for the remaining proteins studied are shown in Supplementary Figs S2-3 and the estimated complexes are shown in Fig. 3 and Supplementary Fig. S4.

Bottom Line: Therefore a systematic way to extract dimerization signals has been elusive.For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively.This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827.

ABSTRACT
We develop a procedure to characterize the association of protein structures into homodimers using coevolutionary couplings extracted from Direct Coupling Analysis (DCA) in combination with Structure Based Models (SBM). Identification of dimerization contacts using DCA is more challenging than intradomain contacts since direct couplings are mixed with monomeric contacts. Therefore a systematic way to extract dimerization signals has been elusive. We provide evidence that the prediction of homodimeric complexes is possible with high accuracy for all the cases we studied which have rich sequence information. For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively. This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation. The identification of dimeric complexes can provide interesting molecular insights in the construction of large oligomeric complexes and be useful in the study of aggregation related diseases like Alzheimer's or Parkinson's.

No MeSH data available.


Related in: MedlinePlus